Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition

BMS906024, a gamma-secretase inhibitor that blocks Notch signaling, was previously shown to inhibit Cryptosporidium parvum growth in vitro. A structure-activity relationship (SAR) analysis of BMS906024 reported herein demonstrates the importance of the stereochemistry of the C-3 benzodiazepine and the succinyl beta-sub-stituent. However, concomitant removal of the succinyl alpha-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC50 = 6.4 nM and an EC90 = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities.

Automated summary

In this study, a structure-activity relationship analysis of BMS906024 revealed that the stereochemistry of the C-3 benzodiazepine and the succinyl beta-substituent play a crucial role in inhibiting Cryptosporidium parvum growth. However, removal of the succinyl alpha-substituent and switching the primary amide with secondary amides was still tolerated. It was also found that inhibition of C. parvum growth was correlated with Notch signaling inhibition, suggesting that further SAR analysis is necessary to differentiate these two activities.